This grant will continue work on the dynamic relation between brain neurotransmitters and movement. Previous work in this laboratory has shown that concentrations of dopamine and DOPAC in anterodorsal striatum and nucleus accumbens of the rat show specific increases in direct relation to the speed, direction, and posture of animals when they perform sustained locomotor activity on straight and circular treadmills. When trained animals run in circles for a water reward they have increases in dopamine, DOPAC, and tyrosine hydroxylase activity in striatum on the side of brain contralateral to the circling direction. Similar contralateral changes are seen in nucleus accumbens, globus pallidus, frontal cortex, and cingulate cortex. By contrast, limbic structures such as medial prefrontal cortex, lateral septal nucleus and ventrolateral striatum show increases in dopamine production on the ipsilateral side. These changes seem to be related to motivation or reward since animals running on treadmills do not show changes in limbic dopamine turnover. Future experiments will explore possible dynamic changes in other transmitters believed involved in striatal function. Acetylcholine, GABA, and glutamate release will be measured in anterodorsal striatum, nucleus accumbens, and substantia nigra in trained circling rats and in rats running on treadmills. Hippocampal acetylcholine release will also be studied in the same movement paradigm. To see if dopamine is released by the firing of dopamine cells in substantia nigra zona compacta, recordings will be made of neuronal firing in this region in cats, and the time course of firing will be related to the time course of dopamine release in striatum. The importance of motor and prefrontal cortex to movement and to striatal dopamine release will be studied by lesioning cortex and then studying dopamine release and trained circling behavior. The ability of fetal nigral grafts to restore normal motor behavior to trained but substantia nigra-lesioned rats will be studied. These experiments will establish the importance of nigral afferents at regulating dopamine release in striatum.